Effect of IN-1130, a small molecule inhibitor of transforming growth factor-beta type I receptor/activin receptor-like kinase-5, on prostate cancer cells.
OBJECTIVE
Transforming growth factor-beta is a potent immune suppressor that is over expressed by most malignant cells to evade the host immune response. Thus, a potential anticancer therapeutic strategy is the inhibition of transforming growth factor-beta signaling.


METHODS
We investigated the specificity and the antitumor effect of IN-1130, a novel small molecule inhibitor of the transforming growth factor-beta type I receptor ALK-5.


RESULTS
IN-1130 inhibited transforming growth factor-beta induced cell death and gene transcriptional activity in a concentration dependent manner in the human hepatoma cell line HepG2. Simultaneously immunoblot analysis demonstrated that IN-1130 inhibited the Smad2 phosphorylation induced by transforming growth factor-beta. To determine the specificity of IN-1130 for transforming growth factor-beta signaling the effect on active and bone morphogenic protein signaling was subsequently investigated. Results demonstrated that IN-1130 did not inhibit bone morphogenic protein signaling. However, active signaling was blocked by IN-1130 in a concentration dependent manner. Furthermore, immunoblot analysis for phospho-Smad2 following transfection with constitutively active ALK-1 to 7 demonstrated that IN-1130 inhibited ALK-4 (active receptor type IB), 5 (TbetaRI) and 7 (nodal type I receptor). To investigate the antitumor effect of IN-1130 WT mice were injected subcutaneously with the murine prostate cancer cell line Tramp C2. Seven days later IN-1130 was administered intraperitoneally daily for 30 days. Results demonstrated a dramatic decrease in tumor volume in association with an enhanced immune response in the treatment group.


CONCLUSIONS
Taken together these results demonstrate that IN-1130 is a relatively nontoxic inhibitor of ALK-4/5/7 that may potentially treat prostate cancer.
Lee
Geun Taek
GT
Division of Urologic Oncology, Cancer Institute of New Jersey and Robert Wood Johnson Medical School, New Brunswick, New Jersey 08903, USA.
Hong
Jun Hyuk
JH
Mueller
Thomas J
TJ
Watson
John A
JA
Kwak
Cheol
C
Sheen
Youn Young
YY
Kim
Dae-Kee
DK
Kim
Seong Jin
SJ
Kim
Isaac Yi
IY
D000818:Animals; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D011471:Prostatic Neoplasms / Q000473:pathology*; D011810:Quinoxalines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
C530153:3-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)benzamide; D007093:Imidazoles; D011810:Quinoxalines